Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that causes chronic inflammation of the joints. RA affects about 1.5 million Americans and costs society more than $40 billion each year. Despite advances in therapy, RA has no cure. Current treatments of RA include non-steroidal anti- inflammatory drugs, corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs). They all have multiple shortcomings including a high level of serious side effects and insufficient efficacy. Methotrexate (MTX), a folate antagonist that blocks folic acid activity, is the most widely used non-biologic DMARD. However, its significant toxicity which is usually related to the dose taken drastically limits its clinical use and is the most common cause of discontinuing MTX therapy. Biologic DMARDs include tumor necrosis factor (TNF) blockers such as Humira. TNF blockers may cause serious side effects such as infections and malignancies. This highlights the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1), an inflammation amplifier, is involved in RA. TREM-1 expression is increased in the synovium of RA patients. In animals, blockade of TREM-1 attenuates inflammation and exerts significant therapeutic effects on collagen-induced arthritis (CIA) without affecting the ability to fight infections. Current approaches to TREM-1 suggest to block binding of ligand to TREM-1. The true nature of the TREM-1 ligand is not yet known, highly increasing the risk of failure of these approaches in clinical development. The long-term objective of the proposed project is to develop a novel, ligand-independent approach to a TREM-1-targeted treatment of RA. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel mechanism-based inhibitory peptides suppresses systemic inflammation and ameliorates arthritis in animal model system of RA. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test TREM-1 inhibitory peptides in a mouse model system. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These non-toxic peptides employ ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to sites of inflammation, we will utilize SignaBlk's proprietary nanosystem for macrophage- specific delivery. We will use the CIA mouse model of RA to test the ability of the peptides in free and particulate forms to inhibit production of pro-inflammatory cytokines and to ameliorate arthritis. It is anticipated that the proposed research will identify novel anti-rheumatic lead compounds that will set the stage for the development of new targeted low-toxic therapies of RA, thereby improving RA treatment and decreasing long-term disability. If successful, the Phase I will be followed in the Phase II by toxicology, absorption/disposition/metabolism/excretion (ADME), pharmacology and chemistry/ manufacturing/ control (CMC) studies, filing an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) and subsequent evaluation in humans. Importantly, the proposed macrophage- specific nanoparticles is a versatile multifunctional delivery platform. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable for targeted delivery of anti- rheumatic combination therapies and diagnostics for RA.